Tropomyosin-related kinase receptors (Trk) are activated by neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 and 4/5 (NT3, NT4/5). Trk regulates neuronal development, survival differentiation and synaptic plasticity (Nikoletopoulou V. et al., 2010, Nature 467:59-63; Chao M. V., 2003, Nat Rev Neurosci 4:299-309). Neurotrophins initiate their cellular responses by binding their specific Trk subtypes. NGF is specific for TrkA, whereas BDNF and NT4/5 are specific for TrkB. NT3 primarily activates TrkC but also other Trk with less efficiency. Neurotrophins binding to Trk induces Trk dimerization and autophosphorylation at specific tyrosine residues in the cytoplasmic domain. This creates docking sites for adaptor proteins that activate PI3K/Akt, MEK/ERK, and PLCγ signaling pathways (Huang E. J. and Reichardt L. F., 2003, Annu Rev Biochem 72:609-642). Formation of Trk/neurotrophin complex also initiates endocytosis required for some biological functions of neurotrophins (Grimes M. L. et al., 1996, J Neurosci 16:7950-7964; Zheng J. et al., 2008, J Biol Chem 283:13280-132).
TrkB and its endogenous ligand BDNF are also important components for the regulation of energy balance and eating behavior in mammals. In previous studies we and other authors have demonstrated that BDNF and its TrkB are downstream mediators of the MC4R (Xu B. et al., 2003, Nat Neurosci 6:736-742; Nicholson J. R. et al., 2007, J Neuroendocrinol 19:974-982; Bariohay B. et al., 2009, Endocrinology 150:2646-2653). In humans, genetic dysfunction of either TrkB or MC4R leads to hyperphagia and obesity (Yeo G. S. et al., 2004, Nat Neurosci 7:1187-1189).
ScFv antibody fragments represent the next generation of biologics (Kontermann R. E., 2010, Curr Opin Mol Ther 176-183). Due to their small size compared with the whole antibody, they are able to cross the blood/brain barrier (Peter J. C. et al., 2010, J Pharmacol Exp Ther 478-490).